PARP Inhibitors as Radiosensitizers: Current Evidence and Future Directions.

Area of Science:

• Oncology
• Radiation Oncology
• Cancer Biology

Background:

• Radiotherapy is crucial for cancer treatment but faces limitations due to tumor radioresistance and normal tissue toxicity.
• Poly(ADP-ribose) polymerase inhibitors (PARPi) are potent radiosensitizers that enhance cancer cell killing by inhibiting DNA repair pathways.
• Ionizing radiation (IR) modalities include X-rays, gamma rays, alpha particles, beta particles, protons, and carbon ions.

Purpose of the Study:

• To synthesize preclinical and clinical evidence on combining PARPi with various IR modalities for cancer treatment.
• To evaluate the therapeutic potential of PARPi plus IR across diverse tumor types.
• To identify future research directions for optimizing PARPi and IR combinations.

Main Methods:

• Structured literature search for preclinical and clinical studies.
• Narrative synthesis of existing evidence.
• Analysis of combination efficacy based on radiation type, DNA repair capacity, and PARPi pharmacodynamics.

Main Results:

• PARPi consistently enhance radiosensitivity, with effects varying by radiation type and tumor characteristics.
• High-linear energy transfer (LET) radiation, such as carbon ions, shows enhanced efficacy in specific contexts.
• Emerging evidence suggests PARPi plus IR can modulate the immune response via the cGAS-STING pathway.
• Clinical trials demonstrate feasibility, but toxicity varies by tumor type and regimen.

Conclusions:

• PARPi combined with radiotherapy represent a promising strategy for improving cancer treatment outcomes.
• Biomarker-driven patient stratification and triple-combination therapies are key areas for future research.
• Optimizing PARPi plus IR combinations requires further investigation into efficacy and toxicity profiles.